Facile and highly diastereoselective synthesis of 3-aminooxindoles via AgOAc-catalyzed vinylogous Mannich reaction

Article abstract of DOI:10.1016/j.tet.2012.02.046

A novel AgOAc-catalyzed vinylogous Mannich reaction between easily prepared imines 1 derived from isatins and trimethylsilyloxyfuran 2 (TMSOF) was developed. This method provided a facile synthetic route to get access to synthetically useful quaternary 3-aminooxindole in excellent yields (94-99%) and diastereoselectivities (>99:1).

Full text of DOI:10.1016/j.tet.2012.02.046

Tetrahedron 68 (2012) 3649e3653
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Facile and highly diastereoselective synthesis of 3-aminooxindoles via
AgOAc-catalyzed vinylogous Mannich reaction
*
Yu-Hua Shi, Zheng Wang, Ying Shi, Wei-Ping Deng
School of Pharmacy and Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel AgOAc-catalyzed vinylogous Mannich reaction between easily prepared imines 1 derived from
isatins and trimethylsilyloxyfuran 2 (TMSOF) was developed. This method provided a facile synthetic
route to get access to synthetically useful quaternary 3-aminooxindole in excellent yields (94e99%) and
diastereoselectivities (>99:1).
Received 24 November 2011
Received in revised form 14 February 2012
Accepted 21 February 2012
Available online 8 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Vinylogous Mannich reaction,8 emerged as a powerful tool for
carbonecarbon bond formation in organic synthesis, and has gained
Oxindole, bearing a C3-quaternary center, is a common and im-
portant core structural motif found in many natural products and
biologicallyactive compounds.1 Amongthem, 3-amino-3-substituted
oxindoles have attracted much attention for their prominent bi-
ological activity in the field of medicinal chemistry,2 including the
potent gastrin/CCK-B receptor antagonist AG-041R2a and the vaso-
pressin VIb receptor antagonist SSR-1494152b,c (Fig. 1). Although
a great deal of effort has been dedicated to the synthesis of such
increasing attention due to its facile access to complicated and
highly functionalized -amino compounds. Vinylogous Mannich
reaction of trimethylsilyloxyfuran (TMSOF) and ketoimine would
constitute an efficient strategy (Scheme 1), affording two stereo-
genic centers, onewith N-substituted quaternarycarbon stereogenic
d
center, appended to a g-butenolide. Ketoimines derived from isatin,
compared with aldimines, are often relatively unreactive, containing
a stericallycongested C]N bond. To the best of our knowledge, there
are only two reported examples of such vinylogous Mannich re-
actions. In 2009, Dodd and his co-workers reported a vinylogous
Mannich reaction between isoquinolines and TMSOF using acyl/
sulfonyl chlorides as activating reagent.9 In the same year, Snapper
and Hoveyda reported the first asymmetric vinylogous Mannich
important structure motif, including intramolecular
amides,3 alkylationof3-aminooxindole,4 Strecker reaction,5 Mannich
addition,6 and direct -amination of 3-substituted oxindoles,7 de-
a-arylation of
a
veloping a new synthetic method is of considerable importance and
still remains a great challenge since the increasing demand for the
varieties of quaternary 3-aminooxindoles in drug discovery.
reaction of TMSOF to a-ketoimine esters with high diastereo- and
enantioselectivity.10 However, a vinylogous Mannich reaction of
isatin-based ketoimine and TMSOF for the synthesis of quaternary 3-
aminooxindoles is still unknown. Herein, we would like to report
a facile AgOAc-catalyzed vinylogous Mannich reaction of ketoimines
derived from isatin and TMSOF, affording quaternary 3-substituted
3-aminooxindoles in high diastereoselectivity.
Scheme 1. Vinylogous Mannich reaction of ketoimine and TMSOF.
Fig. 1. Selected bioactive quaternary aminooxindoles and a related natural compound.
2. Results and discussion
The readily available ketoimines 1 were easily prepared by
condensation of isatins with corresponding aniline, respectively,
followed by N atom protection (Scheme 2).11,12
* Corresponding author. Tel./fax: þ86 021 64252431; e-mail address: wei-
ping_deng@ecust.edu.cn (W.-P. Deng).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.046

3650
Y.-H. Shi et al. / Tetrahedron 68 (2012) 3649e3653
Table 2
Solvent screening
Scheme 2. Synthesis of N-protected isatin-based imines 1.
With the ketoimines 1 in hand, the model reaction of 1a and 2
was chosen for the catalysts and reaction conditions screening
(Table 1).
Entry
Solvent
Yield (%)
dr (anti/syn)
1
2
3
4
5
6
7
8
THF
98
91
89
64
99/1
99/1
99/1
99/1
99/1
d
CHCl3
CH2Cl2
CH3CN
Toluene
Et2O
Table 1
Catalysts screeninga
87
trace
trace
trace
EtOAc
CCl4
d
d
Table 3
AgOAc-catalyzed vinylogous Mannich reaction of 1 and 2
Entry
Metal
Yield (%)
dr (anti/syn)d
1
d
d
d
2
3
4
5
6
7
8
9
10
11
12
13
14b
15c
AgOAc
AgOTf
AgBF4
98
31
99/1
99/1
d
trace
36
trace
trace
trace
36
trace
trace
92
Cu(OAc)2$H2O
Cu(OTf)2
Cu(acac)2
CuCl2$2H2O
Zn(OAc)2$2H2O
Zn(OTf)2
Ni(OAc)2$4H2O
Sc(OTf)3
Yb(OTf)3
AgOAc
99/1
d
d
d
Entry
R1
R2
R3
Yield (%)
dr (anti/syn)
99/1
d
1(1a)
2(1b)
3(1c)
4(1d)
5(1e)
6(1f)
7(1g)
8(1h)
9(1i)
C6H5
C6H5
H
H
H
H
H
H
5-Br
5-Cl
5-Me
H
Bn
allyl
Bn
Bn
Bn
Bn
Bn
Bn
Bn
H
98
99
98
98
97
94
99
99
99
90
99/1
99/1
99/1
99/1
99/1
99/1
99/1
99/1
99/1
99/1
d
4-BreC6H5
4-CleC6H5
4-MeOeC6H5
2-MeOeC6H5
C6H5
C6H5
C6H5
4-CleC6H5
99/1
99/1
99/1
99/1
48
92
73
AgOAc
a
The reaction was carried out in 0.1 mmol scale in the presence of 10 mol % of
metal catalyst.
b
c
AgOAc (5 mol %) was used, and 3 h was required.
AgOAc (2 mol %) was used, and 6 h was required.
The dr of isolated product were determined by 1H NMR.
10(1j)
d
(entries 7e9) gave corresponding product 3gei in quantitative
yields. It is notable that the N-unprotected isatin imine 1j was also
reactive to TMSOF affording corresponding product 3j in slightly
lower yield (Table 3, entry 10, 90%).
The structure of corresponding products 3 was deduced by
X-ray diffraction of a single crystal of 3c as shown in Fig. 2, and the
relative configuration were assigned as the anti isomer.
To our delight, AgOAc was the optimal catalyst to catalyze the
reaction smoothly10,13 and afforded 3-aminooxindole in nearly
quantitative yield in THF at room temperature (Table 1, entry 2). It
was worth noting that no desired product was detected in the
absence of AgOAc catalyst under the same condition (entry 1), and
other silver salts were found to be much less active for this reaction
(entries 3, 4). A variety of metal salts, such as copper, zinc, nickel,
and so on, were also tested in the model vinylogous Mannich re-
action, and most of them were found not suitable to give corre-
sponding product in low yields, except for Sc(OTf)3 (Table 1, entry
12). Decreasing the AgOAc catalyst loading to 5 mol % gave the
product in 92% yield, but a prolonged reaction time 3 h was re-
quired (entry 14). And moderate yield (73%) was obtained when
2 mol % AgOAc was used (entry 15).
Next, solvent effect was also investigated for this reaction
(Table 2). THF was found optimal solvent and all other tried solvents
gave inferior yields or no product for the reaction (entries 2e8).
With the optimized conditions in hand, a variety of ketoimines
were next explored to investigate the generality of this novel re-
action, and the detailed results were presented in Table 3. The
protection group on nitrogen atom was found to have no effect on
the reactivity (Table 3, entries 1, 2). Gratifyingly, either electron-
donating or withdrawing groups on phenyl group of R1 showed
similar reactivities to afford corresponding products 3cef in ex-
cellent yields (Table 3, entries 3e6). Furthermore, the yield of the
reaction was not affected by the substituted group on oxindole,
either the electron-withdrawing group or electron-donating one
Fig. 2. ORTEP view and atom numbering scheme for 3c.
Accordingly, the plausible mechanism was depicted in Fig. 3.
According to well-known AgOAc bifunctional mechanism,14 Ag(I)
acts as the Lewis acid to coordinate 2 equiv of substrate 3a, as well
as the base after coordinating to TMSOF and releasing OAcꢀ, which
is real base to capture the TMS group and consequently activate

Y.-H. Shi et al. / Tetrahedron 68 (2012) 3649e3653
3651
1180,1103,1083, 852, 751, 701, 626, 535 cmꢀ1; HRMS (EI, m/z): calcd
for C21H16N2O: 312.1263, found: 312.1266.
4.2.2. (Z)-1-Allyl-3-(phenylimino)indolin-2-one (1b). Yellow solid;
yield 80% (two steps); mp 102e103 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.43 (t, J¼7.8 Hz, 2H), 7.37e7.29 (m, 1H), 7.26e7.21 (m, 1H), 7.01 (d,
J¼7.4 Hz, 2H), 6.86 (d, J¼7.9 Hz, 1H), 6.75 (t, J¼7.6 Hz, 1H), 6.63 (d,
J¼7.5 Hz, 1H), 5.99e5.77 (m, 1H), 5.45e5.20 (m, 2H), 4.45 (d,
J¼5.3 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 163.0,154.3,150.3,147.2,
134.1, 130.8, 129.4, 126.2, 125.3, 122.7, 118.2, 117.7, 115.7, 110.2, 42.5;
IR (KBr) n 3433, 3205, 1728, 1657, 1605, 1468, 1401, 1374, 1355, 1197,
Fig. 3. Possible transition state for the formation of anti-3a.
934, 754, 700 cmꢀ1; HRMS (EI, m/z): calcd for C17H14N2O: 262.1106,
found: 262.1109.
TMSOF. The stereochemistry of resulting transition state (Fig. 3)
was responsible for the exclusive anti-diastereoslectivity.
4.2.3. (Z)-1-Benzyl-3-(4-bromophenylimino)indolin-2-one
(1c). Yellow solid; yield 89% (two steps); mp 183e185 ꢁC; 1H NMR
(400 MHz, CDCl3)
d
7.56 (d, J¼8.7 Hz, 2H), 7.41e7.26 (m, 6H), 6.93 (d,
J¼8.7 Hz, 2H), 6.80e6.67 (m, 3H), 5.01 (s, 2H); 13C NMR (100 MHz,
3. Conclusion
CDCl3)
d 163.2, 154.6, 149.1, 147.3, 135.0, 134.5, 132.6, 129.0, 128.0,
In conclusion, a facile vinylogous Mannich reaction of ketoi-
mines derived from isatin and TMSOF was developed in the pres-
ence of AgOAc. The protocol provided a new and efficient synthesis
of quaternary 3-amine-3-substituted oxindoles in excellent yields
(94e99%) and diastereoselectivities (>99:1), which is the essential
core structural motif in natural products and biologically active
compounds. Further transformation of these products into a variety
of oxindole-based alkaloid natural products and its asymmetric
synthesis are presently in progress.
127.5, 126.2, 122.9, 119.8, 118.5, 115.6, 110.5, 44.1; IR (KBr)
n 3422,
3178, 1737, 1651, 1612, 1477, 1466, 1401, 1378, 1348, 843, 757,
645 cmꢀ1; HRMS (EI, m/z): calcd for C21H15BrN2O: 390.0368, found:
390.0365.
4.2.4. (Z)-1-Benzyl-3-(4-chlorophenylimino)indolin-2-one
(1d). Yellow solid; yield 84% (two steps); mp 199e200 ꢁC; 1H NMR
(400 MHz, CDCl3)
6.80e6.70 (m, 3H), 5.01 (s, 2H); 13C NMR (100 MHz, CDCl3)
154.7, 148.6, 147.3, 135.0, 134.4, 130.8, 129.7, 129.0, 128.0, 127.5,
126.2, 122.8, 119.4, 115.6, 110.5, 44.1; IR (KBr) 3442, 3409, 1737,
1612, 1480, 1466, 1378, 1349, 1082, 844, 757, 705, 650, 634 cmꢀ1
d
7.44e7.27 (m, 8H), 6.99 (d, J¼8.6 Hz, 2H),
d
163.2,
n
4. Experiment
4.1. General
;
HRMS (EI, m/z): calcd for C21H15ClN2O: 346.0873, found: 346.0875.
4.2.5. (Z)-1-Benzyl-3-(4-methoxyphenylimino)indolin-2-one
All reagents and solvents were used as purchased if not other-
wise stated. Melting points were obtained on a micro melting ap-
paratus SGW X-4 and uncorrected. HRMS (EI) spectra were
obtained on a Finigann MAT8401 instrument. 1H NMR spectra were
recorded on a Bruker DPX 400 MHz spectrometer in chloroform-
d or DMSO-d6. 13C NMR spectra were recorded on a Bruker DPX
100 MHz spectrometer in chloroform-d or DMSO-d6. Chemical shift
values are reported in parts per million on the scale (dTMS¼0).
Diastereomeric ratios were determined from 1H NMR. Infrared
spectra were recorded on NICOLET 5SXC instrument as thin film;
frequencies are given as wavenumbers (cmꢀ1).
(1e). Yellow solid; yield 78% (two steps); mp 158e160 ꢁC; 1H NMR
(400 MHz, CDCl3)
7.09e7.04 (m, 2H), 6.99e6.93 (m, 3H), 6.78e6.72 (m, 2H), 5.02 (s,
2H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3)
163.6, 157.8, 153.7,
147.0, 143.0, 135.2, 133.8, 128.9, 127.9, 127.5, 125.7, 122.6, 120.2,
d
7.40e7.28 (m, 5H), 7.22 (dd, J¼7.8, 1.0 Hz, 1H),
d
116.0, 114.5, 110.3, 55.5, 44.0; IR (KBr)
n 3409, 2930, 1720, 1599,
1500, 1470, 1354, 1293, 1247, 1186, 1162, 1104, 1034, 762, 731 cmꢀ1
;
HRMS (EI, m/z): calcd for C22H18N2O2: 342.1368, found: 342.1371.
4.2.6. (Z)-1-Benzyl-3-(2-methoxyphenylimino)indolin-2-one
(1f). Yellow solid; yield 75% (two steps); mp 134e136 ꢁC; 1H NMR
(400 MHz, CDCl3)
(m, 3H), 6.76e6.70 (m, 3H), 5.01 (s, 2H), 3.76 (s, 3H); 13C NMR
(100 MHz, CDCl3) 163.3, 155.0, 148.3, 146.9, 139.1, 135.2, 133.9,
128.9, 127.9, 127.5, 126.5, 125.8, 122.8, 121.1, 119.3, 116.7, 111.8, 110.1,
55.7, 44.0; IR (KBr) 3445, 3021, 2906, 1730, 1610, 1591, 1490, 1471,
1454, 1378, 1354, 1251, 1182, 1114, 1018, 774, 759, 735, 695,
456 cmꢀ1; HRMS (EI, m/z): calcd for C22H18N2O2: 342.1368, found:
342.1370.
d 7.41e7.29 (m, 5H), 7.25e7.18 (m, 2H), 7.02e6.99
4.2. General procedure for the synthesis of imines 111,12
d
To a solution of isatin (14.7 g, 0.1 mol, 1.0 equiv) and aniline
(0.15 mol, 1.5 equiv) in absolute ethanol was added 2e3 drops of
acetic acid, and the reaction was heated to reflux for about 3 h. The
residue was recrystallized to afford the imine as a yellowish solid.
The ketoimines (1.0 equiv) derived from isatin reacted with alkyl
bromide (2.0 equiv) in the presence of K2CO3 (2.0 equiv) and tet-
rabutylammonium bromide (0.1 equiv) in DMF. After stirred over-
night at room temperature, cold water was added to the mixture
and the precipitate was filtrated, which was further purified by re-
crystallization from ethanol.
n
4.2.7. (Z)-1-Benzyl-5-bromo-3-(phenylimino)indolin-2-one
(1g). Yellow solid; yield 87% (two steps); mp 154e155 ꢁC; 1H NMR
(400 MHz, CDCl3)
d
7.48 (t, J¼7.5 Hz, 2H), 7.40e7.29 (m, 7H), 7.04 (d,
J¼7.8 Hz, 2H), 6.75 (s, 1H), 6.65 (d, J¼8.3 Hz, 1H), 5.02 (s, 2H); 13C
NMR (100 MHz, CDCl3)
d 162.8, 153.0, 149.7, 145.9, 136.5, 134.6,
4.2.1. (Z)-1-Benzyl-3-(phenylimino)indolin-2-one
(1a). Yellow
129.6, 129.1, 128.9, 128.1, 127.4, 126.0, 119.4, 117.7, 115.3, 111.9, 44.1;
solid; yield 86% (two steps); mp 139e140 ꢁC; 1H NMR (400 MHz,
IR (KBr)
n 3425, 3080, 1726, 1602, 1471, 1443, 1334, 1178, 826, 725,
CDCl3)
d
7.48e7.29 (m, 7H), 7.26e7.17 (m, 2H), 7.04e7.00 (m, 2H),
693, 611 cmꢀ1; HRMS (EI, m/z): calcd for C21H15BrN2O: 390.0368,
6.78e6.68 (m, 2H), 6.63 (d, J¼7.6 Hz, 1H), 5.01 (s, 2H); 13C NMR
found: 390.0366.
(100 MHz, CDCl3)
d 163.4, 154.3, 150.3, 147.1, 135.1, 134.1, 129.5,
129.0, 128.0, 127.5, 126.2, 125.4, 122.8, 117.8, 115.8, 110.4, 44.0; IR
(KBr) 3431, 2922, 1731, 1605, 1593, 1466, 1377, 1356, 1344, 1321,
4.2.8. (Z)-1-Benzyl-5-chloro-3-(phenylimino)indolin-2-one
n
(1h). Yellow solid; yield 84% (two steps); mp 157e158 ꢁC; 1H NMR

3652
Y.-H. Shi et al. / Tetrahedron 68 (2012) 3649e3653
(400 MHz, CDCl3)
d
7.47 (t, J¼7.4 Hz, 2H), 7.37e7.28 (m, 6H), 7.20 (d,
1340, 1259, 1181, 1153, 1107, 1081, 1050, 889, 818, 755, 695,
513 cmꢀ1; HRMS (EI, m/z): calcd for C25H20N2O3: 396.1474, found:
396.1476.
J¼8.4 Hz, 1H), 7.02 (d, J¼7.7 Hz, 2H), 6.68 (d, J¼8.3 Hz, 1H), 6.60 (s,
1H), 5.01 (s, 2H); 13C NMR (100 MHz, CDCl3)
162.9, 153.2, 149.7,
145.5, 134.6, 133.6, 129.6, 129.0, 128.1, 127.4, 126.1, 126.0, 119.4, 117.7,
116.7, 111.4, 44.1; IR (KBr) 3449, 3076, 1725, 1656, 1602, 1470,1442,
1402,1369,1352,1333,1178,1126,1081, 826, 811, 780, 725, 693, 624,
514 cmꢀ1; HRMS (EI, m/z): calcd for C21H15ClN2O: 346.0873, found:
346.0876.
d
n
4.4.2. 1-Allyl-3-(5-oxo-2,5-dihydrofuran-2-yl)-3-(phenylamino)in-
dolin-2-one (3b). Off-white solid; yield 99%; mp 185e186 ꢁC; 1H
NMR (400 MHz, CDCl3)
d
7.59 (dd, J¼5.8, 1.4 Hz, 1H), 7.43e7.33 (m,
2H), 7.14e7.07 (m, 1H), 6.99 (t, J¼7.9 Hz, 2H), 6.92 (d, J¼7.8 Hz, 1H),
6.77 (t, J¼7.4 Hz, 1H), 6.37 (d, J¼7.7 Hz, 2H), 6.29 (dd, J¼5.8, 1.9 Hz,
1H), 5.81e5.70 (m, 1H), 5.37e5.30 (m, 1H), 5.26e5.09 (m, 2H), 4.64
4.2.9. (Z)-1-Benzyl-5-methyl-3-(phenylimino)indolin-2-one
(1i). Yellow solid; yield 80% (two steps); mp 137e138 ꢁC; 1H NMR
(br s, 1H), 4.43e4.31 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
173.9,
171.2,151.2,144.1,142.7,130.6,130.4,129.0,125.6,124.7,124.5,123.0,
121.0, 118.2, 117.6, 110.0, 84.7, 66.9, 42.7; IR (KBr) 3302, 3063, 1792,
(400 MHz, CDCl3)
d
7.51e7.27 (m, 8H), 7.04 (d, J¼7.1 Hz, 3H), 6.64 (d,
J¼7.9 Hz, 1H), 6.42 (s, 1H), 5.01 (s, 2H), 2.03 (s, 3H); 13C NMR
n
(100 MHz, CDCl3)
d
163.5, 154.5, 150.4, 144.9, 135.2, 134.4, 132.2,
1768, 1700, 1613, 1600, 1499, 1487, 1467, 1432, 1379, 1358, 1339,
1306, 1256, 1189, 1153, 1108, 1086, 1047, 924, 896, 816, 752, 692,
655, 508 cmꢀ1; HRMS(EI, m/z): calcd for C21H18N2O3: 346.1317,
found: 346.1316.
129.4, 128.9, 127.9, 127.5, 126.8, 125.3, 117.8, 115.8, 110.1, 44.0, 20.9;
IR (KBr) n 3056, 3028, 2925,1728,1658,1608, 1591, 1480, 1454,1433,
1355, 1342, 1185, 1123, 828, 759, 694, 634 cmꢀ1; HRMS (EI, m/z):
calcd for C22H18N2O: 326.1419, found: 326.1423.
4.4.3. 1-Benzyl-3-(4-bromophenylamino)-3-(5-oxo-2,5-
4.3. Procedure for the synthesis of TMSOF 215
dihydrofuran-2-yl)indolin-2-one (3c). Off-white solid; yield 98%;
mp 228e230 ꢁC; 1H NMR (400 MHz, DMSO)
d
8.08 (dd, J¼5.8,
A 1-L three-necked flask, equipped with a reflux condenser and
a dropping funnel, was charged with furfural (48 g, 0.5 mol), CH2Cl2
(250 mL), formic acid (46 g, 1.0 mol), Na2SO4 (50 g), and K2CO3
(17.5 g). The mixture was vigorously stirred and 30% H2O2 (38 mL)
was added in one portion. Vigorous stirring was continued for
30e45 min after which refluxed gently. Then 30% H2O2 (63 mL) was
added dropwise with continued stirring. The mixture was stirred
overnight after cooling to room temperature. The organic phase
was separated, and the aqueous layer was extracted with 50 mL
CH2Cl2. The combined organic phase was concentrated in vacuo.
100 mL toluene was added and formic acid was removed by
azeotropic distillation. Another 100 mL toluene was added to the
reisdue, followed by 1.3 mL triethylamine, and the mixture was
allowed to stand for 1 h. After toluene was evaporated, the residual
liquid was distilled in vacuo to afford furanone (19.7 g, 47%) as
colorless liquid at 63e66 ꢁC/5.9 mmHg.
1.3 Hz, 1H), 7.42e7.25 (m, 6H), 7.07e6.96 (m, 6H), 6.39 (dd, J¼5.8,
1.8 Hz, 1H), 6.16 (d, J¼8.9 Hz, 2H), 5.62 (t, J¼1.5 Hz, 1H), 5.01 (s,
2H); 13C NMR (100 MHz, DMSO)
d 175.0, 171.5, 154.5, 145.2, 143.4,
136.3, 131.8, 130.6, 129.0, 128.0, 125.7, 123.7, 123.6(7), 122.6(2),
116.9, 110.4, 109.8, 84.1, 66.4, 43.8; IR (KBr) 3342, 2963, 2923,
n
1751, 1716, 1613, 1593, 1530, 1488, 1467, 1369, 1349, 1330, 1315,
1261, 1180, 1106, 1074, 1023, 912, 801, 753, 698, 499 cmꢀ1; HRMS
(EI, m/z): calcd for C25H19BrN2O3: 474.0579, found: 474.0582.
Crystals of 3c were monoclinic, space group P2(1)/c; empirical
ꢀ
formula C25H19BrN2O3, formula weight, 475.33; a¼14.0369(12) A,
ꢀ
ꢀ
b¼13.8239(12) A, c¼11.0121(10) A,
a
¼90ꢁ,
b
¼95.6150(10)ꢁ,
3
ꢀ
g
¼90ꢁ, V¼2126.3(3) A ; T¼123(2) K;
l
¼0.71073 A; Z¼4,
ꢀ
Dcalcd¼1.485
g
cmꢀ3
;
F(000)¼968,
m
¼1.963 mmꢀ1
; Crystal
size¼0.35ꢂ0.30ꢂ0.20 mm; reflections collected, 13,838; unique
reflections
(Rint¼0.0154),
4151;
wR2¼0.0745(all
data),
R1¼0.0249(I>2
s
(I)); Data in the
q
range 1.46e26.00ꢁ were col-
To furanone (19.7 g, 0.142 mol) Et3N (36.0 mL, 0.26 mol) was
added, followed by TMSCl (19.7 g, 0.235 mol) at 0 ꢁC under N2. The
reaction mixture was filtrated through silica gel, and the cake was
washed with dry Et2O to give a clear filtrate. Fractional distillation
under reduced pressure of the mixture afforded 2 (13.0 g, 58%) as
a yellowish liquid at 76e78 ꢁC/27 mmHg (lit. 44e46 ꢁC/17 mmHg).
lected at 123(2) K on a Bruker Apex CCD diffractometer. The
structure was solved by direct methods and refined by full-matrix
least-squares using all F2 data.
4.4.4. 1-Benzyl-3-(4-chlorophenylamino)-3-(5-oxo-2,5-
dihydrofuran-2-yl)indolin-2-one (3d). Off-white solid; yield 98%;
1H NMR (400 MHz, CDCl3)
d
6.83e6.81 (m, 1H), 6.22e6.20 (m,
mp 247e249 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.48 (dd, J¼5.8, 1.4 Hz,
1H), 5.11 (d, J¼3.1 Hz, 1H), 0.30 (s, 9H).
1H), 7.38e7.34 (m, 1H), 7.32e7.27 (m, 4H), 7.11e7.04 (m, 3H),
6.95e6.86 (m, 2H), 6.80 (d, J¼7.9 Hz, 1H), 6.33e6.22 (m, 3H), 5.34
(d, 1.6 Hz, 1H), 5.06 (d, J¼15.5 Hz, 1H), 4.70 (d, J¼15.5 Hz, 1H), 4.60
4.4. Typical procedure for vinylogous Mannich reaction
(s, 1H); 13C NMR (100 MHz, CDCl3)
d 173.8, 171.0, 150.9, 142.6(3),
To a solution of imines 1 derived from isatin (0.1 mmol,
1.0 equiv) and anhydrous AgOAc (1.6 mg, 0.01 mol, 0.1 equiv) in
142.6(2), 134.8, 130.7, 129.0, 128.8, 128.0, 127.5, 126.5, 125.5, 124.7,
124.4, 123.3, 119.7, 110.2, 84.6, 67.1, 44.2; IR (KBr) 3344, 3323,
n
1 mL THF was added 2-(trimethylsilyloxy)furan (TMSOF) (34
m
L,
2925,1789, 1762, 1747, 1705, 1611, 1598, 1528, 1489, 1466, 1374, 1347,
1314, 1256, 1179, 1152, 1105, 1084, 1047, 889, 816, 749, 698,
502 cmꢀ1; HRMS (EI, m/z): calcd for C25H19ClN2O3: 430.1084,
found: 430.1088.
0.2 mmol, 2.0 equiv), and then the reaction was stirred for 1 h. The
solvent was removed in vacuo and the residue was purified by flash
chromatography (petroleum ether/EtOAc¼4/1 to 2/1) to afford the
product as a gray-white or white solid.
4.4.5. 1-Benzyl-3-(4-methoxyphenylamino)-3-(5-oxo-2,5-
4.4.1. 1-Benzyl-3-(5-oxo-2,5-dihydrofuran-2-yl)-3-(phenylamino)in-
dihydrofuran-2-yl)indolin-2-one (3e). Off-white solid; yield 97%;
dolin-2-one (3a). Off-white solid; yield 98%; mp 204e206 ꢁC; 1H
mp 187e189 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.59 (dd, J¼5.8, 1.2 Hz,
NMR (400 MHz, CDCl3)
d
7.45 (dd, J¼5.8, 1.5 Hz, 1H), 7.30 (d,
1H), 7.40 (d, J¼7.4 Hz, 1H), 7.25e7.14 (m, 4H), 7.06 (t, J¼7.5 Hz, 1H),
6.95e6.84 (m, 2H), 6.63 (d, J¼7.8 Hz, 1H), 6.60e6.43 (m, 4H), 6.27
(dd, J¼5.8, 1.9 Hz, 1H), 5.39 (t, J¼1.5 Hz, 1H), 5.05 (d, J¼15.8 Hz, 1H),
4.60 (d, J¼15.8 Hz, 1H), 4.26 (br s, 1H), 3.68 (s, 3H); 13C NMR
J¼7.5 Hz, 1H), 7.20e7.11 (m, 4H), 7.08e6.97 (m, 3H), 6.89 (t,
J¼7.9 Hz, 2H), 6.72 (t, J¼8.1 Hz, 2H), 6.37e6.26 (m, 2H), 6.20 (dd,
J¼5.8, 2.0 Hz, 1H), 5.26 (t, J¼1.7 Hz, 1H), 4.98 (d, J¼15.6 Hz, 1H), 4.66
(d, J¼15.6 Hz, 1H), 4.44 (br s, 1H); 13C NMR (100 MHz, DMSO)
(100 MHz, CDCl3)
d 174.6, 171.5, 155.8, 151.7, 143.3, 136.9, 135.0,
d
175.4, 171.5, 154.7, 145.9, 143.4, 136.3, 130.4, 129.2, 129.0, 128.0,
130.6, 128.8, 127.8, 127.3, 126.1, 124.7, 124.6, 123.4, 123.1, 114.4, 110.3,
84.9, 68.7, 55.5, 44.1; IR (KBr) 3313, 2898, 1791, 1768, 1692, 1609,
1513, 1485, 1466, 1435,1374,1289, 1247, 1180, 1158, 1107, 1079,1028,
127.9, 125.7, 124.1, 123.6, 122.5, 118.6, 114.8, 110.3, 84.2, 66.4, 43.7; IR
(KBr) 3300, 3065, 2924, 1792, 1768, 1692, 1603, 1489, 1469, 1374,
n
n

Y.-H. Shi et al. / Tetrahedron 68 (2012) 3649e3653
3653
892, 816, 758, 732, 700, 638, 518 cmꢀ1; HRMS (EI, m/z): calcd for
C26H22N2O4: 426.1580, found: 426.1579.
J¼4.4 Hz, 2H), 6.20 (dd, J¼5.8, 1.8 Hz, 1H), 5.36 (d, J¼12.0 Hz, 1H);
13C NMR (100 MHz, CD3CN)
175.0, 170.9, 152.1, 143.9, 141.4, 130.1,
128.4, 125.1, 124.1, 123.5, 123.1, 121.9, 116.0, 110.4, 83.8, 66.2.; IR
(KBr) 3285, 1802, 1759, 1707, 1622, 1492, 1471, 1326, 1252, 1204,
1164, 1089, 1043, 901, 823, 810, 754, 734, 711, 689, 662, 641 cmꢀ1
d
4.4.6. 1-Benzyl-3-(2-methoxyphenylamino)-3-(5-oxo-2,5-
dihydrofuran-2-yl)indolin-2-one (3f). Off-white solid; yield 94%;
n
;
mp 187e189 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.63 (dd, J¼5.8, 1.2 Hz,
HRMS (EI, m/z): calcd for C18H13ClN2O3: 340.0615, found: 340.0620.
1H), 7.34e7.24 (m, 7H), 7.02 (t, J¼7.5 Hz, 1H), 6.84 (d, J¼8.0 Hz, 1H),
6.75 (d, J¼7.3 Hz, 1H), 6.70e6.64 (m, 1H), 6.41e6.35 (m, 1H), 6.27
(dd, J¼5.8, 1.8 Hz, 1H), 5.73 (dd, J¼7.9, 0.8 Hz, 1H), 5.35 (s, 1H), 5.21
(br s, 1H), 5.07 (d, J¼15.5 Hz, 1H), 4.82 (d, J¼15.5 Hz, 1H), 3.87 (s,
Acknowledgements
This work was financially supported by the Natural Science
Foundation of China (No. 20972047), the ‘Shu Guang’ project of
Shanghai Municipal Education Commission, Shanghai Education
Development Foundation (No. 09SG28), the Fundamental Research
Funds for the Central Universities and the Shanghai Committee of
Science and Technology (No. 11DZ2260600).
3H); 13C NMR (100 MHz, CDCl3)
d 174.3, 171.1, 151.3, 148.1, 142.5,
135.2,134.1,130.3,128.8,127.9,127.8,125.6,125.1,124.4,123.1,120.8,
119.7, 113.5, 110.0(4), 109.9(7), 84.9, 66.2, 55.7, 44.4; IR (KBr) 3377,
n
2927, 1784, 1757, 1714, 1601, 1510,1544,1436, 1458, 1258, 1228,1176,
1147, 1077, 1038, 1021, 889, 818, 734, 698, 580, 516 cmꢀ1; HRMS (EI,
m/z): calcd for C26H22N2O4: 426.1580, found: 426.1582.
Supplementary data
4.4.7. 1-Benzyl-5-bromo-3-(5-oxo-2,5-dihydrofuran-2-yl)-3-(phe-
nylamino)indolin-2-one (3g). Off-white solid; yield 99%; mp
The copies of 1H NMR and 13C NMR of the compounds 3 are
found in the Supplementary data. Supplementary data associated
with this article can be found, in the online version, at doi:10.1016/
j.tet.2012.02.046.
179e182 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.58 (d, J¼5.7 Hz, 1H), 7.47
(d, J¼1.6 Hz, 1H), 7.39 (dd, J¼8.3, 1.8 Hz, 1H), 7.29e7.26 (m, 3H),
7.15e7.06 (m, 2H), 6.99 (t, J¼7.8 Hz, 2H), 6.83 (t, J¼7.4 Hz, 1H), 6.66
(d, J¼8.3 Hz, 1H), 6.38e6.28 (m, 3H), 5.37e5.25 (m, 1H), 5.07 (d,
J¼15.6 Hz, 1H), 4.71 (d, J¼15.6 Hz, 1H), 4.51 (br s, 1H); 13C NMR
(100 MHz, CDCl3)
d 173.7, 170.9, 150.8, 143.7, 141.6, 134.5, 133.4,
References and notes
129.2, 128.9, 128.7, 128.0, 127.5, 126.9, 124.8, 121.5, 117.9, 116.0, 111.6,
84.4, 67.0, 44.4; IR (KBr) 3317, 2920, 2854, 1791, 1768, 1700, 1600,
€
1. (a) Antonchick, A. P.; Gerding-Reimers, C.; Catarinella, M.; Schurmann, M.;
n
Preut, H.; Ziegler, S.; Rauh, D.; Waldmann, H. Nature Chem. 2010, 2, 735; (b)
Nicolaou, K. C.; Chen, D. Y.-K.; Huang, X.; Ling, T.; Bella, M.; Snyder, S. A. J. Am.
Chem. Soc. 2004, 126, 12888; (c) Netz, A.; Oost, T.; Geneste, H.; Braje, W. M.;
Wernet, W.; Unger, L.; Hornberger, W.; Lubisch, W. PTC Int. Appl.
WO2008080971, 2008; (d) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed.
2007, 46, 8748.
1499, 1479, 1425, 1360, 1341, 1313, 1256, 1182, 1149, 1098, 1080,
1045, 892, 883, 820, 751, 699, 633, 536 cmꢀ1; HRMS (EI, m/z): calcd
for C25H19BrN2O3: 474.0579, found:474.0585.
4.4.8. 1-Benzyl-5-chloro-3-(5-oxo-2,5-dihydrofuran-2-yl)-3-(phe-
2. (a) Ochi, M.; Kawasaki, K.; Kataoka, H.; Uchio, Y.; Nishi, H. Biochem. Biophys. Res.
Commun. 2001, 283, 1118; (b) Bernard, K.; Bogliolo, S.; Ehrenfeld, J. Br. J. Phar-
macol. 2005, 144, 1037; (c) Decaux, G.; Soupart, A.; Vassart, G. Lancet 2008, 371,
1624; (d) Claudine, S. G.; Sylvain, D.; Gilles, G.; Claudine, S. L. Stress 2003, 6, 199;
(e) Takayama, H.; Mori, I.; Kitajima, M.; Aimi, N.; Lajis, N. H. Org. Lett. 2004, 6,
2945.
nylamino)indolin-2-one (3h). Off-white solid; yield 99%; mp
208e210 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.61 (d, J¼5.7 Hz, 1H), 7.35
(s, 1H), 7.27e7.22 (m, 4H), 7.15e7.10 (m, 2H), 7.01 (t, J¼7.6 Hz, 2H),
6.84 (t, J¼7.3 Hz, 1H), 6.73 (d, J¼8.4 Hz, 1H), 6.44e6.29 (m, 3H), 5.33
(s, 1H), 5.10 (d, J¼15.6 Hz, 1H), 4.73 (d, J¼15.6 Hz, 1H), 4.52 (s, 1H);
€
3. (a) Jia, Y.-X.; Hillgren, J. M.; Watson, M. L.; Marsden, S. P.; Kundig, E. P. Chem.
Commun. 2008, 4040; (b) Marsden, S. P.; Watson, M. L.; Raw, S. A. Org. Lett.
2008, 10, 2905.
4. (a) Emura, T.; Esaki, T.; Tachibana, K.; Shimizu, M. J. Org. Chem. 2006, 71, 8559;
(b) Zhao, H.; Thurkauf, A.; Braun, J.; Brodbeck, R.; Kieltyka, A. Bioorg. Med. Chem.
Lett. 2000, 10, 2119.
13C NMR (100 MHz, CDCl3)
d 173.8, 170.9, 150.8, 143.7, 141.1, 134.5,
130.5, 129.3, 128.9, 128.8, 128.0, 127.5, 126.5, 126.0, 124.8, 121.5,
117.9, 111.1, 84.4, 67.0, 44.4; IR (KBr) 3325, 2917, 2852, 1790, 1768,
n
1700, 1601, 1499, 1484, 1433, 1329, 1314, 1254, 1181, 1148, 1100,
1082, 1047, 889, 824, 753, 698, 618, 547 cmꢀ1; HRMS (EI, m/z): calcd
for C25H19ClN2O3: 430.1084, found: 430.1079.
5. Liu, Y.-L.; Zhou, F.; Cao, J.-J.; Ji, C.-B.; Ding, M.; Zhou, J. Org. Biomol. Chem. 2010,
8, 3847.
6. (a) Miyabe, H.; Yamaoka, Y.; Takemoto, Y. J. Org. Chem. 2005, 70, 3324; (b)
Lesma, G.; Landoni, N.; Pilati, T.; Sacchetti, A.; Silvani, A. J. Org. Chem. 2009, 74,
4537; (c) Alcaide, B.; Almendros, P.; Aragoncillo, C. Eur. J. Org. Chem. 2010, 2845;
(d) Nishikawa, T.; Kajii, S.; Isobe, M. Chem. Lett. 2004, 33, 440.
7. (a) Cheng, L.; Liu, L.; Wang, D.; Chen, Y.-J. Org. Lett. 2009, 11, 3874; (b) Qian, Z.-
Q.; Zhou, F.; Du, T.-P.; Wang, B.-L.; Ding, M.; Zhao, X.-L.; Zhou, J. Chem. Commun.
4.4.9. 1-Benzyl-5-methyl-3-(5-oxo-2,5-dihydrofuran-2-yl)-3-(phe-
nylamino)indolin-2-one (3i). Off-white solid; yield 99%; mp
203e206 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.48 (d, J¼5.4 Hz, 1H),
ꢁ
2009, 6753; (c) Bui, T.; Hernandez-Torres, G.; Milite, C.; Barbas, C. F., III. Org. Lett.
7.40e7.27 (m, 2H), 7.22e6.85 (m, 7H), 6.81e6.74 (d, J¼7.3 Hz, 1H),
6.70 (d, J¼7.9 Hz, 1H), 6.33 (d, J¼7.8 Hz, 2H), 6.27 (d, J¼5.5 Hz, 1H),
5.31 (s, 1H), 5.04 (d, J¼15.5 Hz, 1H), 4.72 (d, J¼15.5 Hz, 1H), 4.58 (s,
2010, 12, 5696; (d) Mouri, S.; Chen, Z.; Mitsunuma, H.; Furutachi, M.; Matsu-
naga, S.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 1255; (e) Yang, Z.; Wang, Z.;
Bai, S.; Shen, K.; Chen, D.; Liu, X.; Lin, L.; Feng, X. Chem.dEur. J. 2010, 16, 6632.
8. For typical reviews, see: (a) Martin, S. F. Acc. Chem. Res. 2002, 35, 895; (b) Bur, S.
K.; Martin, S. F. Tetrahedron 2001, 57, 3221.
1H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 173.9, 171.3, 151.1,
144.2, 140.0, 135.1, 132.9, 130.8, 129.1, 128.8, 127.8, 127.7, 126.1, 124.9,
124.5, 120.9, 117.4, 109.9, 85.0, 66.8, 44.3, 21.1; IR (KBr) 3308, 2958,
2919, 2854, 1793, 1768, 1700, 1601, 1498, 1439, 1376, 1347, 1315,
1258, 1181, 1154, 1097, 1081, 1047, 892, 826, 809, 749, 737, 693, 626,
505 cmꢀ1; HRMS (EI, m/z): calcd for C21H18N2O3: 410.1630, found:
410.1633.
9. Hermange, P.; Dau, M. E. T. H.; Retailleau, P.; Dodd, R. H. Org. Lett 2009, 11, 4044.
10. Wieland, L. C.; Vieira, E. M.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2009, 131, 570.
11. Rajopadhye, M.; Dopp, F. D. J. Heterocycl. Chem. 1985, 22, 93.
12. Bouhfid, R.; Joly, N.; Massoui, M.; Cecchelli, R.; Lequart, V.; Martin, P.; Assassi, E.
M. Heterocycles 2005, 65, 2949.
n
13. For selected literatures, see: (a) Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2006, 45, 7230; (b) Mandai, H.; Mandai, K.; Snapper, M. L.;
ꢁ
ꢁ
Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130, 17961; (c) Gonzalez, A. S.; Arrayas, R.
G.; Rivero, M. R.; Carretero, J. C. Org. Lett. 2008, 10, 4335; (d) Deng, H.-P.; Wei, Y.;
Shi, M. Adv. Synth. Catal. 2009, 351, 2897.
4.4.10. 3-(4-Chlorophenylamino)-3-(5-oxo-2,5-dihydrofuran -2-yl)
indolin-2-one (3j). Off-white solid; yield 90%; mp 218e220 ꢁC; 1H
14. (a) Zeng, W.; Zhou, Y. G. Org. Lett. 2005, 7, 5055; (b) Chen, Q.-A.; Wang, D.-S.;
Zhou, Y.-G. Chem. Commun. 2010, 4043.
15. Casiraghi, G.; Rassu, G. Synthesis 1995, 607.
NMR (400 MHz, CD3CN)
J¼7.6 Hz,1H), 7.70 (dd, J¼5.6,1.2 Hz,1H), 7.00e6.92 (m, 4H), 6.29 (d,
d
8.76 (br s, 1H), 7.68 (J¼5.6 Hz, 1H), 7.31 (t,